GENETIC EPIDEMIOLOGY OF ALLERGY TO BETALACTAM ANTIBIOTICS

Abstract

Background: Immediate antibiotic allergic response is an important public health problem. Genetic and molecular characterization will improve treatment outcomes for truly allergic patients, and also reduce the use (and risk of evolution of pathogen resistance) of second-line antibiotics given to patients who incorrectly believe themselves to be allergic to first-line antibiotics. Objective: To identify genetic and metabolic factors associated with allergic responses to beta-lactam antibiotics using the TwinsUK cohort and recruited participants from the Guy’s allergy clinic. Methods: The TwinsUK cohort is the largest registry of adult twins in the UK, and the Guy’s allergy clinic is an outsized clinic covering a large area of the UK. The TwinsUK cohort has been extensively molecularly characterized. After characterising the heritability, we conducted the first high-coverage genomewide association study (GWAS) between 211 self-reported cases in the TwinsUK cohort with questionnaire-defined beta-lactam allergic status and over 1000 individuals without self-reported allergic reaction to any substances. Approximately 2.1 million imputed and genotyped single nucleotide polymorphisms were investigated. A second GWAS was conducted on 48 clinically proven cases from the Guy’s Hospital allergy clinic and ~6000 population controls. In addition a metabolome-wide association study (MWAS) was conducted on the same TwinsUK registry individuals, scanning 510 different metabolites. Results: Following refinement of the self-reported beta-lactam allergy phenotype via the application of a more detailed questionnaire, we estimated a heritability of 21%. The heritability estimates provided positive evidence for a genetic component for beta-lactam allergy. A single hit from the TwinsUK GWAS at the MTHFS/BCL2A1 locus was found (p<5x10-8 ), indicating a provisional “genomewide significant” hit. Results from the TwinsUK MWAS demonstrated that all metabolites responded as a correlated system to the differences among twins in their allergy status. There were also 4 distinct “metabolome-wide significant” hits, of which two corresponded to known metabolites, suggesting that people who had penicillin allergy had less piperine in their system in comparison with our control group and had higher amounts of 4-vinylphenol-sulfate metabolite. Conclusion: This study demonstrated a genetic component to beta-lactam allergy, and in particular provided evidence for a genetic signal at the MTFHS/BCL2A1 locus. Although the MWAS study showed that there was a metabolomic difference between the allergic and non-allergic individuals. These findings may lead to new personalised treatments based on a combination of genotyping and metabolic characterization. The findings of our studies need verification in independent cohorts.

Date of Award	2017
Original language	English
Awarding Institution	King's College London
Supervisor	Mike Weale (Supervisor) & Kourosh Rasekh Ahmadi (Supervisor)